Annals of Biomedical Engineering

, Volume 44, Issue 2, pp 276–286 | Cite as

Sustained Efficacy and Arterial Drug Retention by a Fast Drug Eluting Cross-Linked Fatty Acid Coronary Stent Coating

  • Natalie Artzi
  • Abraham R. TzafririEmail author
  • Keith M. Faucher
  • Geoffrey Moodie
  • Theresa Albergo
  • Suzanne Conroy
  • Scott Corbeil
  • Paul Martakos
  • Renu Virmani
  • Elazer R. Edelman
Medical Stents: State of the Art and Future Directions


The long held assumption that sustained drug elution from stent coatings over weeks to months is imperative for clinical efficacy has limited the choice for stent coating materials. We developed and evaluated an omega-3 fatty acid (O3FA) based stent coating that is 85% absorbed and elutes 97% of its Sirolimus analog (Corolimus) load within 8d of implantation. O3FA coated stents sustained drug levels in porcine coronary arteries similarly to those achieved by slow-eluting durable coated Cypher Select Plus Stents and with significantly lower levels of granuloma formation and luminal stenosis. Computational modeling confirmed that diffusion and binding constants of Corolimus and Sirolimus are identical and explained that the sustained retention of Corolimus was facilitated by binding to high affinity intracellular receptors (FKBP12). First in man outcomes were positive—unlike Cypher stents where late lumen loss drops over 6 month, there was a stable effect without diminution in the presence of O3FA. These results speak to a new paradigm whereby the safety of drug eluting stents can be optimized through the use of resorbable biocompatible coating materials with resorption kinetics that coincide with the dissociation and tissue elimination of receptor-bound drug.


Drug eluting stents Sirolimus analogs Computational modeling 



This study was supported in part by grants from the NIH (R01 GM-49039) to ERE and in part by support of animal work and preclinical studies at MIT, CBSET and CVPath. ERE and RV are paid consultants to Atrium. Coauthors KMF, GM, TA, PM, S. Conroy and S. Corbeil are employees of Atrium Medical Corporation and provided input into the study design and editorial input into the writing of the manuscript. Data collection, analysis and interpretation of animal and computer experiments were all performed independent of input from Atrium Medical Corporation. The decision to submit the paper for publication came from joint discussions between Atrium Medical management and all authors. The authors would like to acknowledge Alicia Dale, Roger Labrecque and Jessica Mayer from Atrium Medical Corporation for assistance in executing experimental work to support this publication.

Supplementary material

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Supplementary material 1 (PDF 871 kb)


  1. 1.
    Agrawal, C. M., and K. A. Athanasiou. Technique to control pH in vicinity of biodegrading PLA-PGA implants. J. Biomed. Mater. Res. 38:105–114, 1997.CrossRefPubMedGoogle Scholar
  2. 2.
    Axel, D. I., W. Kunert, C. Goggelmann, M. Oberhoff, C. Herdeg, A. Kuttner, D. H. Wild, B. R. Brehm, R. Riessen, G. Koveker, and K. R. Karsch. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 96:636–645, 1997.CrossRefPubMedGoogle Scholar
  3. 3.
    Buerke, M., M. Guckenbiehl, H. Schwertz, U. Buerke, M. Hilker, H. Platsch, J. Richert, S. Bomm, G. A. Zimmerman, S. Lindemann, U. Mueller-Werdan, K. Werdan, H. Darius, and A. S. Weyrich. Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury. Biochim. Biophys. Acta 1774:5–15, 2007.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Byrne, R. A., R. Iijima, J. Mehilli, S. Pinieck, O. Bruskina, A. Schomig, and A. Kastrati. Durability of antirestenotic efficacy in drug-eluting stents with and without permanent polymer. JACC Cardiovasc. Interv. 2:291–299, 2009.CrossRefPubMedGoogle Scholar
  5. 5.
    Deeken, C. R., K. M. Faucher, and B. D. Matthews. A review of the composition, characteristics, and effectiveness of barrier mesh prostheses utilized for laparoscopic ventral hernia repair. Surg. Endosc. 26:566–575, 2012.CrossRefPubMedGoogle Scholar
  6. 6.
    Drachman, D. E., E. R. Edelman, P. Seifert, A. R. Groothuis, D. A. Bornstein, K. R. Kamath, M. Palasis, D. Yang, S. H. Nott, and C. Rogers. Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. J. Am. Coll. Cardiol. 36:2325–2332, 2000.CrossRefPubMedGoogle Scholar
  7. 7.
    Finn, A. V., F. D. Kolodgie, J. Harnek, L. J. Guerrero, E. Acampado, K. Tefera, K. Skorija, D. K. Weber, H. K. Gold, and R. Virmani. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 112:270–278, 2005.CrossRefPubMedGoogle Scholar
  8. 8.
    Guagliumi, G., H. Ikejima, V. Sirbu, H. Bezerra, G. Musumeci, N. Lortkipanidze, L. Fiocca, S. Tahara, A. Vassileva, A. Matiashvili, O. Valsecchi, and M. Costa. Impact of drug release kinetics on vascular response to different zotarolimus-eluting stents implanted in patients with long coronary stenoses: the LongOCT study (Optical Coherence Tomography in Long Lesions). JACC Cardiovasc. Interv. 4:778–785, 2011.CrossRefPubMedGoogle Scholar
  9. 9.
    Joner, M., A. V. Finn, A. Farb, E. K. Mont, F. D. Kolodgie, E. Ladich, R. Kutys, K. Skorija, H. K. Gold, and R. Virmani. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J. Am. Coll. Cardiol. 48:193–202, 2006.CrossRefPubMedGoogle Scholar
  10. 10.
    Kolandaivelu, K., R. Swaminathan, W. J. Gibson, V. B. Kolachalama, K. L. Nguyen-Ehrenreich, V. L. Giddings, L. Coleman, G. K. Wong, and E. R. Edelman. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 123:1400–1409, 2011.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Neamtu, I., A. P. Chiriac, A. Diaconu, L. E. Nita, V. Balan, and M. T. Nistor. Current concepts on cardiovascular stent devices. Mini Rev. Med. Chem. 14:505–536, 2014.CrossRefPubMedGoogle Scholar
  12. 12.
    NRC (National Research Council). Guide for the Care and Use of Laboratory Animals, 1996.Google Scholar
  13. 13.
    Oberhauser, J. P., S. Hossainy, and R. J. Rapoza. Design principles and performance of bioresorbable polymeric vascular scaffolds. EuroIntervention 5(Suppl F):F15–F22, 2009.CrossRefPubMedGoogle Scholar
  14. 14.
    Ormiston, J., M. Webster, F. De Vroey, S. El Jack, J. Stewart, and P. Ruygrok. Vantage 1 trial: a FIM evaluation of the cinatra corolimus-eluting stent with a bioabsorbable omega-3 fatty acid coating in de novo coronary lesions. Heart Lung Circ. 20:414, 2011.CrossRefGoogle Scholar
  15. 15.
    Parker, T., V. Dave, and R. Falotico. Polymers for drug eluting stents. Curr. Pharm. Des. 16:3978–3988, 2010.CrossRefPubMedGoogle Scholar
  16. 16.
    Rogers, C., and E. R. Edelman. Endovascular stent design dictates experimental restenosis and thrombosis. Circulation 91:2995–3001, 1995.CrossRefPubMedGoogle Scholar
  17. 17.
    Rorabacher, D. B. Statistical treatment for rejection of deviant values: critical values of Dixon’s “Q” parameter and related subrange ratios at the 95% confidence level. Anal. Chem. 63:139–146, 1991.CrossRefGoogle Scholar
  18. 18.
    Schwartz, R. S., E. R. Edelman, A. Carter, N. Chronos, C. Rogers, K. A. Robinson, R. Waksman, J. Weinberger, R. L. Wilensky, D. N. Jensen, B. D. Zuckerman, and R. Virmani. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group. Circulation 106:1867–1873, 2002.CrossRefPubMedGoogle Scholar
  19. 19.
    Shazly, T., V. B. Kolachalama, J. Ferdous, J. P. Oberhauser, S. Hossainy, and E. R. Edelman. Assessment of material by-product fate from bioresorbable vascular scaffolds. Ann. Biomed. Eng. 40:955–965, 2012.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Strom, T., T. Shokati, J. Klawitter, K. Hoffman, H. M. Schiebel, and U. Christians. Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns. J. Mass Spectrom. 46:615–624, 2011.CrossRefPubMedGoogle Scholar
  21. 21.
    Tanigawa, J., P. Barlis, K. Dimopoulos, M. Dalby, P. Moore, and C. Di Mario. The influence of strut thickness and cell design on immediate apposition of drug-eluting stents assessed by optical coherence tomography. Int. J. Cardiol. 134:180–188, 2009.CrossRefPubMedGoogle Scholar
  22. 22.
    Tzafriri, A. R., A. D. Levin, and E. R. Edelman. Diffusion-limited binding explains binary dose response for local arterial and tumour drug delivery. Cell Prolif. 42:348–363, 2009.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Tzafriri, A. R., N. Vukmirovic, V. B. Kolachalama, I. Astafieva, and E. R. Edelman. Lesion complexity determines arterial drug distribution after local drug delivery. J. Control Release 142:332–338, 2010.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Tzafriri, A. R., A. Groothuis, G. S. Price, and E. R. Edelman. Stent elution rate determines drug deposition and receptor-mediated effects. J. Control Release 161:918–926, 2012.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Virmani, R., F. Liistro, G. Stankovic, C. Di Mario, M. Montorfano, A. Farb, F. D. Kolodgie, and A. Colombo. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans. Circulation 106:2649–2651, 2002.CrossRefPubMedGoogle Scholar
  26. 26.
    Virmani, R., G. Guagliumi, A. Farb, G. Musumeci, N. Grieco, T. Motta, L. Mihalcsik, M. Tespili, O. Valsecchi, and F. D. Kolodgie. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 109:701–705, 2004.CrossRefPubMedGoogle Scholar
  27. 27.
    Wilson, G. J., G. Nakazawa, R. S. Schwartz, B. Huibregtse, B. Poff, T. J. Herbst, D. S. Baim, and R. Virmani. Comparison of inflammatory response after implantation of sirolimus- and paclitaxel-eluting stents in porcine coronary arteries. Circulation 120(141–9):1–2, 2009.Google Scholar
  28. 28.
    Wilson, G. J., A. Marks, K. J. Berg, M. Eppihimer, N. Sushkova, S. P. Hawley, K. A. Robertson, D. Knapp, D. E. Pennington, Y. L. Chen, A. Foss, B. Huibregtse, and K. D. Dawkins. The SYNERGY biodegradable polymer everolimus eluting coronary stent: porcine vascular compatibility and polymer safety study. Catheter. Cardiovasc. Interv. 2015. doi: 10.1002/ccd.25993.PubMedCentralGoogle Scholar

Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  • Natalie Artzi
    • 1
    • 2
  • Abraham R. Tzafriri
    • 1
    • 3
    Email author
  • Keith M. Faucher
    • 4
  • Geoffrey Moodie
    • 4
  • Theresa Albergo
    • 4
  • Suzanne Conroy
    • 4
  • Scott Corbeil
    • 4
  • Paul Martakos
    • 4
  • Renu Virmani
    • 5
  • Elazer R. Edelman
    • 1
    • 6
  1. 1.Institute for Medical Engineering and ScienceMassachusetts Institute of TechnologyCambridgeUSA
  2. 2.Department of Anesthesiology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  3. 3.Department of Applied ScienceCBSET Inc.LexingtonUSA
  4. 4.MAQUET Vascular Systems (Formerly Atrium Medical Corporation)MerrimackUSA
  5. 5.CV Path InstituteGaithersburgUSA
  6. 6.Cardiovascular Division, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

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